To understand the physical chemical basis of nerve excitation, we are studying the relationships between changes in temperature and volume associated with nerve excitability. We are continuing to explore the possibility that divalent/monovalent cation exchange can induce such changes. To investigate this hypothesis, we are studying ion exchange in biomolecular assemblies, and in synthetic biomimetic anionic polymer gels under nearly physiological solution conditions. An advantage of studying the behavior of these gel model systems is that their structure, composition, and the interactions among their components can be carefully controlled, unlike in living tissue. In particular, in synthetic polyacrylate gels, Ferenc Horkay has observed that minute changes in the concentration of divalent cations in the surrounding liquid can induce significant changes in chain stiffness in the gel, even if ion binding is weak and completely reversible. Various physical chemical and polymer physics-based techniques, including neutron, x-ray and light scattering, as well as osmotic swelling, and mechanical loading provide complementary information with which to study these biologically relevant phenomena over a wide range of length scales. These basic studies are leading to a deeper understanding of the physical mechanisms underlying nerve excitation. [unreadable] [unreadable] In trying to understand the biophysical basis of the diffusion MR signal, Uri Nevo has successfully constructed and tested an experimental system for interrogating organotypic cultured brain slices using diffusion MRI methods. This work has already shown promising results relating changes in the measured diffusion coefficient map to changes in environmental conditions to which the cultured tissue is subjected. A theoretical aspect of this work is the development of model systems in which we can demonstrate how microscopic flows manifest themselves as "pseudo-diffusion" and manifest themselves as signal loss in diffusion weighted MRI experiments.[unreadable] [unreadable] In the area of Transcranial Magnetic Stimulation (TMS), Pedro Miranda and his group, in association with STBB has performed detailed calculations using finite element methods (FEM), to predict the electric field and current density distributions induced in the brain during magnetic stimulation. Previously, we found that both tissue heterogeneity and anisotropy of the electrical conductivity contribute significantly to distort the induced fields, and even to create excitatory or inhibitory hot spots in some regions. These phenomena could have significant clinical consequences both in interpreting or inferring the region or locus of excitation and in determining the source of nerve excitation. More recently, we have focussed on possible physical mechanisms of cortical excitation. A longer term goal is to marry our macroscopic models of magnetic stimulation in nerve tissue with microscopic models of nerve excitability in the CNS and PNS. More detailed FEM models of TMS in the cortex are under development.